Drugs in Pregnancy and Lactation: Tenth Edition

IDARUBICIN

Antineoplastic

PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk

BREASTFEEDING RECOMMENDATION: Contraindicated

PREGNANCY SUMMARY

Limited pregnancy experience, all in the 2nd trimester, suggests that idarubicin may cause significant fetal toxicity. Exposure during organogenesis has not been reported.

FETAL RISK SUMMARY

Idarubicin, an anthracycline antineoplastic antibiotic agent, is a DNA-intercalating analog of daunorubicin. It is used in the treatment of acute myeloid leukemia. It is in the same antineoplastic subclass of anthracyclines as daunorubicin, doxorubicin, epirubicin, and valrubicin.

In pregnant rats, a dose 10% of the human dose (HD) produced embryotoxicity and teratogenicity without causing maternal toxicity. Embryotoxicity, but not teratogenicity, occurred in rabbits treated with doses up to about 20% of the HD. However, this dose caused maternal toxicity (1).

Shepard (2) reviewed three reproductive studies in which IV doses up to 0.2 mg/kg were given to rats. When treatment occurred early in pregnancy, fetal loss, intrauterine growth restriction (IUGR), decreased ossification, and skeletal defects such as fused ribs were observed at the highest dose. These effects were not seen when treatment occurred perinatally. Infertility may have occurred in the second generation.

A 26-year-old woman at 20 weeks’ gestation who presented with acute myeloblastic leukemia, was treated with an induction course of cytarabine and daunorubicin that failed to halt the disease progression (3). At approximately 23 weeks’ gestation, a second induction course was started with mitoxantrone and cytarabine. Complete remission was achieved 60 days from the start of therapy. Weekly ultrasound examinations documented normal fetal growth. Because of the long interval required for remission, treatment was changed to idarubicin (10 mg/m2, days 1 and 2) and cytarabine. She tolerated this therapy and was discharged home, but returned 2 days later complaining of abdominal pain and the loss of fetal movements. A stillborn, 2200-g fetus (gestational age not specified) without evidence of congenital malformations was delivered after induction. Permission for an autopsy was denied. Although the authors did not specify a mechanism, they concluded that the cause of the fetal death was due to idarubicin.

A 1998 case report described a woman with acute myeloid leukemia who was treated with idarubicin and cytarabine during the 2nd trimester (4). Treatment was begun at 21 weeks’ gestation with IV idarubicin 10 mg/m2 on days 1, 3, and 5 and IV cytarabine 100 mg/m2 on days 1–10. A 6-day consolidation course of IV cytarabine, 1000 mg/m2 every 12 hours, was given 6 weeks later. Complete remission was documented after recovery from this course. IUGR and decreased fetal movements were diagnosed at 32 weeks’ gestation and a week and half later, a 1408-g female infant was delivered by cesarean section. Apgar scores were 4, 7, and 10 at 1, 5, and 10 minutes, respectively. Except for hyperbilirubinemia, the infant was healthy and was doing well on discharge. An echocardiographic examination revealed no evidence of cardiac anomalies or signs of cardiomyopathy (4).

A 22-year-old woman at 22 weeks’ gestation with acute lymphoblastic leukemia type T was treated with idarubicin (9 mg/m2 on days 1, 2, 3, and 8), cyclophosphamide (750 mg/m2 on days 1 and 8), vincristine (2 mg/day on days 1, 8, 15, and 22), and prednisone (60 mg/m2 on days 1–7 and 15–21) (5). The patient tolerated the therapy except for agranulocytosis with fever, which was treated with antibiotics. A complete remission was documented by 27 weeks’ gestation. Before consolidation chemotherapy, a 1024-g male infant was delivered by cesarean section 1 week later. Apgar scores were 6, 8, and 8 at 1, 5, and 10 minutes, respectively. Neonatal complications, related to prematurity, were respiratory distress syndrome, necrotizing enterocolitis, and grade II ventricular hemorrhage (5). In addition, acute heart failure occurred during the first 3 days after birth (5). Diffuse cardiomyopathy involving both ventricles and the interventricular septum without anomalies was revealed by echocardiography. The condition was thought to be related to the chemotherapy, especially, idarubicin. With supportive care, the cardiac function returned to normal within 3 days. Except for slight delay in the acquisition of language, the infant was progressing normally at 18 months of age (5).

In a 2009 case report, a woman with relapse of acute myeloid leukemia at 22 weeks’ gestation was treated with idarubicin, fludarabine, cytarabine, mitoxantrone, and gemtuzumab ozogamicin (6). The fetus developed signs of idarubicin-induced cardiomyopathy, transient cerebral ventriculomegaly, anemia, and intrauterine growth restriction. The newborn, delivered at 33 weeks’ by cesarean section, showed no congenital malformations.

Occupational exposure of the mother to antineoplastic agents during pregnancy may present a risk to the fetus. A position statement from the National Study Commission on Cytotoxic Exposure and a research article involving some antineoplastic agents are presented in the monograph for cyclophosphamide (see Cyclophosphamide).

BREASTFEEDING SUMMARY

No reports describing the use of idarubicin during lactation have been located. The molecular weight (about 498 for the free base) is low enough that excretion into breast milk should be expected. Because of the potential toxicity, a woman treated with this drug should not breastfeed until idarubicin and its cytoxic and presumed active metabolite, idarubicinol, have been eliminated from her system. Idarubicin has a mean terminal half-life of 20–22 hours (range 4–46 hours), but the estimated mean terminal half-life of idarubicinol exceeds 45 hours (1). Thus, elimination of the two agents may require 10 days or longer. The American Academy of Pediatrics classifies similar antineoplastic agents (e.g., doxorubicin) as contraindicated during breastfeeding because of the potential for immune suppression and an unknown effect on growth or association with carcinogenesis (7).

References

1.Product information. Idamycin. Pharmacia, 1996.

2.Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: The Johns Hopkins University Press, 1995:1290.

3.Reynoso EE, Huerta F. Acute leukemia and pregnancy—fatal fetal outcome after exposure to idarubicin during the second trimester. Acta Oncol 1994;33:703–16.

4.Claahsen HL, Semmekrot BA, van Dongen PWJ, Mattijssen V. Successful fetal outcome after exposure to idarubicin and cytosine-arabinoside during the second trimester of pregnancy—a case report. Am J Perinatol 1998;15:295–7.

5.Achtari C, Hohlfeld P. Cardiotoxic transplacental effect of idarubicin administered during the second trimester of pregnancy. Am J Obstet Gynecol 2000;183:511–2.

6.Baumgartner AK, Oberhoffer R, Jacobs VR, Ostermayer E, Menzel H, Voigt M, Schneider KT, Pildner von Steinburg S. Reversible foetal cerebral ventriculomegaly and cardiomyopathy under chemotherapy for maternal AML. Onkologie 2009;32:40–3.

7.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.